Impact of corticosteroid doses on prognosis of severe and critical COVID-19 patients with Omicron variant infection: a propensity score matching study

Background There is lack of research on corticosteroid use for severe and critical COVID-19 patients with Omicron variant infection. Methods This multi-center retrospective cohort study involved 1167 patients from 59 ICUs across the mainland of China diagnosed with severe or critical SARS-CoV-2 Omicron variant infection between November 1, 2022, and February 11, 2023. Patients were segregated into two groups based on their corticosteroid treatment—usual dose (equivalent prednisone dose 30–50 mg/day) and higher dose (equivalent prednisone dose > 50 mg/day). The primary outcome was 28-day ICU mortality. Propensity score matching was used to compare outcomes between cohorts. Results After propensity score matching, 520 patients in the usual dose corticosteroid group and 260 patients in the higher dose corticosteroid group were included in the analysis, respectively. The mortality was significantly higher in the higher dose corticosteroid group (67.3%, 175/260) compared to the usual dose group (56.0%, 291/520). Logistic regression showed that higher doses of corticosteroids were significantly associated with increased mortality at 28-day (OR = 1.62,95% CI 1.19–2.21, p = 0.002) and mortality in ICU stay (OR = 1.66,95% CI 1.21–2.28, p = 0.002). Different types of corticosteroids did not affect the effect. Conclusions The study suggests that higher-dose corticosteroids may lead to a poorer prognosis for severe and critical COVID-19 patients with Omicron variant infection in the ICU. Further research is needed to determine the appropriate corticosteroid dosage for these patients.


Introduction
Corticosteroids are used to treat severe COVID-19 due to their effectiveness in managing inflammation (Lamers & Haagmans 2022;Wu et al. 2020).They are considered essential in the treatment of critically ill patients (Angus et al. 2020;Horby et al. 2021;Tomazini et al. 2020).However, the appropriate dosage for severe or critical cases remains a topic of debate.Studies have shown benefits with doses like dexamethasone 6 mg daily or hydrocortisone 200 mg daily (Angus et al. 2020;Horby et al. 2021).Some studies suggested higher doses such as dexamethasone 10-20 mg per day and methylprednisolone 80 mg per day are also effective (Tomazini et al. 2020;Wu et al. 2020).The question of whether higher doses are more beneficial requires further investigation, as previous studies have provided inconsistent results (Granholm et al. 2022;Group 2023;Munch et al. 2021;Salvarani et al. 2022).
Additionally, the majority of patients in previous studies were infected with SARS-CoV-2 non-Omicron variants, while the Omicron variant has become dominant since 2022.Since severe or critical cases are less common with Omicron variant infection, there is a lack of research on the use of corticosteroids for this specific group.It is important to explore whether higher doses of corticosteroids are necessary for critically ill patients with Omicron variant infections, considering the potential lower inflammatory response.
Therefore, this study aims to explore whether the application of higher doses of corticosteroids (equivalent prednisone doses of > 50 mg per day for the application of dexamethasone, methylprednisolone, prednisone, or prednisolone) compared to the application of usual doses of corticosteroids (equivalent prednisone doses of 30-50 mg per day) conducted a prognostic impact on severe or critical COVID-19 patients with Omicron variant infection through a multi-center retrospective cohort in the mainland of China.

Study design and data collection
This is a multi-center retrospective cohort study including 59 ICUs in the mainland of China.Inclusion criteria were age > 18 years old, confirmed SARS-CoV-2 infection (COVID-19), and classified as severe or critical, requiring ICU care between November 1, 2022, and February 11, 2023.Exclusion criteria included a lack of prognostic information and unclear respiratory support modalities.
All demographic, clinical characteristics, laboratory tests, treatment, and outcome data were collected through electronic medical records and organized in standard data collection forms.All investigators were properly trained before data entry, and all data were reviewed by two supervisors.Because of the observational nature of the study, written informed consent was waived.The study protocol was approved by the Research Ethics Commission of China-Japan Friendship Hospital (2019-79-K51-1).

Diagnostic criteria and definitions
The severity of the disease was based on the Chinese management guideline for COVID-19 (Trial Version 10.0), (China 2023)  Immunosuppressed hosts include patients with primary immunodeficiency, active malignancy receiving treatment, AIDS, solid organ or bone marrow stem cell transplantation, long-term glucocorticoid, and immunosuppressive therapy for primary disease.Respiratory support, vasopressor use, PaO 2 , PaO 2 /FiO 2 ratio (PFR), acute physiology and chronic health evaluation II (APACHE II), and sequential organ failure assessment score (SOFA) scores were the worst conditions or values for the first 24 h of ICU admission.Simple oxygen therapy refers to nasal cannula oxygen support or mask oxygen inhalation.Antiviral therapy prior to ICU admission and in combination includes Paxlovid, azvudine, and molnupiravir.

Outcomes
The primary clinical outcome of the study was 28-day mortality in ICU stay.The secondary clinical outcome was in-ICU mortality.The other admission data included organ dysfunction in ICU stay, secondary infection, septic shock, acute kidney injury, acute myocardial injury, deep venous thrombosis, acute pulmonary embolism, acute liver injury, gastrointestinal bleeding, hyperglycemia, renal replacement therapy in ICU stay, extracorporeal membrane oxygenation (ECMO) in ICU stay.
Secondary infection refers to any infection that occurs beyond 48 h after ICU admission from the blood, respiratory tract, urinary system, or other sterile sites.Septic shock was diagnosed according to the definition provided by the Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2016 (Rhodes et al. 2017).Acute kidney injury was diagnosed based on the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 clinical practice guidelines (Kellum & Lameire 2013).Serum cardiac biomarkers above 99th percentile upper reference limits or an abnormal electrocardiogram or echocardiography were indicators of acute myocardial injury (DeFilippis et al. 2019).Acute liver injury was defined as total bilirubin levels > 171 μmol/L or daily elevations ≥ 17.1 μmol/L and international normalized ratio (INR) ≥ 2.0 (Shen et al. 2019).Hyperglycemia was defined as random blood glucose > 250 mg/dl.

Main exposure
Corticosteroid treatment refers to the administration of corticosteroids (any of methylprednisolone, prednisone, prednisolone, dexamethasone, or hydrocortisone) via oral or intravenous and at least one dose in ICU.The usual dose of corticosteroids was defined as an equivalent prednisone dose of 30-50 mg per day (hydrocortisone 120-200 mg per day, or prednisone/prednisolone 30-50 mg per day, or methylprednisolone 24-40 mg per day, or dexamethasone 4.5-7.5 mg per day).In comparison, the higher dose of corticosteroids was defined as an equivalent prednisone dose higher than 50 mg per day (hydrocortisone > 200 mg per day, or prednisone/prednisolone > 50 mg per day, or methylprednisolone > 40 mg per day, or dexamethasone > 7.5 mg per day).As for the types of corticosteroids, prednisone, prednisolone, and methylprednisolone are all intermediateacting corticosteroids and are classified in one category, while dexamethasone, as a long-acting corticosteroid, is classified in another category.

Statistical analysis
Continuous variables were displayed as mean ± standard deviation if they conformed to normal distribution; continuous variables were expressed as median within the interquartile range (IQR) if they did not conform to normal distribution.The Mann-Whitney test was used for continuous variables.Categorical variables were reported as frequencies and percentages.The Fisher exact test or chi-square tests were conducted to compare binary and categorical variables.
To compare outcomes between two groups of patients who had similar baseline characteristics except for different treatment variables (usual dose and higher dose of corticosteroids).We performed a two-to-one propensity score (PS) matching analysis estimated by logistic regression to account for potential confounding factors.Variables involved in the PS estimation included sex, age, underlying diseases, Immunocompromised condition, respiratory support, vasopressor use, and duration of corticosteroid treatment.Matching was based on the logit of the PS using nearest-neighbor matching (greedy-type matching) with a caliper width of 0.25.After matching, Kaplan-Meier curves were used to track the 28-day mortality for patients receiving the usual or higher dose of corticosteroid therapy.The effect of different doses of corticosteroids on the primary clinical outcome and other outcome events was also explored by univariate logistic regression models.In addition, an extended Cox regression model that treated corticosteroids as a time-varying exposure variable was used to assess the effect of usual or higher doses of corticosteroid treatment on 28-day mortality.The effect of different doses of corticosteroid treatment on 28-day mortality was also performed using Cox regression in the following subgroups: age < 75 years or age ≥ 75 years; different respiratory support status [no oxygen or simple oxygen, high flow nasal cannula (HFNC) or noninvasive positive pressure ventilation (NIPPV), and invasive positive pressure ventilation (IPPV) or ECMO].For multivariate models, different doses and types of corticosteroid treatment were included for analysis.

Results
Between November 1, 2022, and February 11, 2023, 2030 patients diagnosed with severe or critical SARS-CoV-2 Omicron variant infection from 59 ICUs in the mainland of China were enrolled in the study.Twenty patients with missing information on respiratory support conditions and five with unclear prognostic information were excluded.The aim of this study was to determine the prognostic impact of different doses of corticosteroids, 372 patients with vague corticosteroid use (n = 266) and duration of use (n = 106) were excluded.Four hundred and forty-seven patients who had not applied corticosteroids (applied before ICU or with contraindications) or had tapered the dose to less than the usual dose were also excluded.Nineteen patients treated with hydrocortisone were excluded from the analysis due to small numbers.The detailed data-cleaning process is shown in Fig. 1.

Clinical characteristics
Ultimately, 1167 patients with severe or critical SARS-CoV-2 Omicron variant infection were included in the final analysis, with a median age of 75 (IQR 61-82) years and 74.0%(863/1167) male, of whom 907 patients were on usual doses of corticosteroids and 260 patients on higher doses.After the propensity score matching, 520 patients on usual doses of corticosteroids and 260 patients on higher doses were matched (Fig. 1).The balanced data of variables included in the matching model are shown in Fig. 2.

Mortality and other clinical outcomes analysis
After the propensity score matching, we performed logistic regression to determine the impact of higher doses of corticosteroids in patients with severe or critical SARS-CoV-2 Omicron variant infection in the ICU.The median ICU stay was 9 (5-15) and 8 (5-15) days for patients receiving usual doses and higher doses of corticosteroids, respectively.The 28-day all-cause mortality in ICU for all patients was 59.7% (466/780), with 56.0% (291/520) in the usual dose corticosteroid treatment group and 67.3% (175/260) in the higher dose corticosteroid treatment group.Kaplan-Meier curves for 28-day all-cause mortality demonstrated lower survival in patients in the higher dose corticosteroid treatment group (Log Rank p = 0.024) (Fig. 3).Logistic regression showed that higher doses of corticosteroid application were associated with 28-day mortality (OR = 1.62,95%CI 1.19-2.21,p = 0.002).The all-cause in ICU mortality for all patients  To further discuss the effect of higher doses of corticosteroids and different types of corticosteroids on 28-day  mortality and time to death, we performed Cox regression analysis.The results showed that the use of higher doses of corticosteroids was still associated with 28-day mortality (HR 1.234, 95% CI 1.023-1.489,p = 0.028) in patients with severe or critical SARS-CoV-2 Omicron variant infection after the inclusion of time variable and was not related to the type of corticosteroid applied.Application of different types of corticosteroids (dexamethasone or methylprednisolone/prednisolone/prednisolone) had no effect on the 28-day prognosis.In subgroup analysis, no effect of higher doses and different types of corticosteroid application on 28-day mortality was observed in the subgroups of patients with age greater than 75 years old or not and different respiratory support conditions at the time of ICU admission.The detailed data are demonstrated in Table 3.

Discussion
This study aimed to investigate the prognostic impact of varying corticosteroid doses on patients with severe or critical SARS-CoV-2 Omicron variant infection.The propensity score matching analysis demonstrated that higher doses of corticosteroids were associated with increased 28-day mortality in this group of patients, irrespective of the type of corticosteroid used.
The publication of the RECOVERY trial established the cornerstone role of corticosteroids (dexamethasone 6 mg daily for no more than ten days) in the treatment of COVID-19, especially in critically ill patients requiring higher respiratory support conditions (Horby et al. 2021).Several subsequent studies have clarified that corticosteroids can improve the prognosis of patients with severe or critical COVID-19 to a certain degree (Sterne et al. 2020).Based on the results of these clinical trials, the World Health Organization and National Institutes of Health guidelines for the treatment of COVID-19 strongly recommend the use of corticosteroids in patients with critically ill COVID-19 (Health 2023;Organization 2023).However, the doses of corticosteroids applied in different trials are not uniform, e.g., dexamethasone 6 mg daily and 20 mg daily may both improve the prognosis, which creates confusion in clinical practice because higher doses of corticosteroids may bring more management challenges such as secondary infections, hyperglycemia, and gastrointestinal bleeding, especially in critically ill patients admitted to the ICU (Horby et al. 2021;Tomazini et al. 2020).Therefore, several subsequent studies have explored whether higher than 6 mg of dexamethasone or equivalent doses of other types of corticosteroids can provide a prognostic benefit compared to usual doses.The STEROID 2 trial, an international parallel randomized controlled trial, showed that 12 mg of dexamethasone daily did not significantly improve the 28-day life support-free rate and 180-day mortality in patients with severe COVID-19 compared to 6 mg of dexamethasone daily, but the results favored higher doses of dexamethasone (Granholm et al. 2022;Munch et al. 2021).However, the newly published RECOVERY trial showed that higher doses of dexamethasone (20 mg dexamethasone daily for 5 days, then tapered to 10 mg dexamethasone daily for 5 days for a total of no more than 10 days) resulted in an increased risk of death in patients with COVID-19 who were hypoxic but did not require mechanical ventilation compared to usual doses of dexamethasone (6 mg dexamethasone daily for no more than 10 days) (Group 2023).Another randomized double-blind controlled trial in patients with severe COVID-19 treated with methylprednisolone pulse therapy (1 g applied for 3 days) on top of usual dexamethasone therapy (6 mg dexamethasone daily for no more than 10 days) showed no prognostic benefit from higher doses of corticosteroids (Salvarani et al. 2022).Other relatively small studies also do not provide an answer to the question of whether higher doses of corticosteroids provide a prognostic benefit for patients with severe COVID-19, but the limited data suggested that higher doses of corticosteroids may be harmful (Katz et al. 2023;Toroghi et al. 2022;Yaqoob et al. 2022).Our study explored whether higher doses of corticosteroids (greater than 50 mg equivalent prednisone dose per day), using 30 to 50 mg equivalent prednisone per day as the usual doses, resulted in a prognostic benefit in patients with severe or critical COVID-19 admitted to the ICU.The results showed a higher 28-day all-cause mortality in this group of patients.This result is not contradictory to previous studies and further indicates that higher doses of corticosteroids in patients with severe or critical COVID-19 do not lead to improved prognosis.
With the continuous mutation of the SARS-CoV-2 virus, the Omicron variant is gradually replacing other variant strains as the mainstream strain of the current epidemic.Several large-scale studies have suggested that the Omicron variant caused less severe disease than the Delta variant in adults admitted to the hospital with SARS-CoV-2 infection but still resulted in high mortality (Bouzid et al. 2022;Català et al. 2022;Iuliano et al. 2022;Lauring et al. 2022).In patients admitted to the ICU, the mortality of the Omicron variant infection was not inferior to that of the Delta variant (de Prost et al. 2022).These results demonstrated that previous immunizations and vaccines might attenuate the severity of critically ill COVID-19 caused by the SARS-CoV-2 Omicron variant and that once severe or critical disease is caused by infection with the Omicron variant, the severity is not inferior to that of infection with other variants.Our study showed that patients who were critically ill and required ICU treatment due to SARS-CoV-2 Omicron variant infection had a mortality that was not inferior to that of the Alpha and Delta variant infections, which may support the above inference to some extent (Do et al. 2023;Grasselli et al. 2020).The presence of underlying disease in 94.2% of our cohort may also account for the poor prognosis of this group of patients, and similar findings have been reported in other studies (Piralla et al. 2023).
In addition, there are very limited studies on the application of corticosteroid therapy in patients with severe or critical COVID-19 due to the SARS-CoV-2 Omicron variant.Our results suggested that the application of higher doses (greater than the equivalent prednisone dose of 50 mg/d) of corticosteroids in this group of patients may lead to a poor prognosis, indicating that the application of corticosteroids in these patients should be more conservative.The reason for this finding is unknown, and a milder systemic inflammatory response due to infection with the SARS-CoV-2 Omicron variant may be one of the plausible explanations (Bojkova et al. 2022;Du et al. 2022).Besides, the median age of patients in this study reached 75 years.The possibility that elderly patients with critically ill COVID-19 may benefit less from corticosteroid therapy may be another reason for this result (Jung et al. 2021).
Our study had limitations.Firstly, it was a retrospective study with limited ICU bed availability, making the enrolled patients not fully representative of all critically ill patients.Propensity score matching was used to achieve comparability between the groups, but some patients had missing laboratory test results.Inconsistent detection reagents and ranges for certain tests further affected the analysis.Additionally, accurately obtaining the duration and dose of corticosteroids prior to ICU admission was challenging due to the study's retrospective nature, which could impact result interpretation.Secondly, it was a nonrandomized controlled study with initial differences in clinical characteristics between the groups.Although propensity score matching was performed, unmeasured or unknown confounders may still affect the results.Furthermore, the study focused only on clinical endpoints and outcomes within the ICU, without analyzing long-term outcomes.

Conclusions
The study concluded that in severe or critical COVID-19 patients with Omicron variant infection, higher doses of corticosteroids were associated with increased 28-day and in-ICU mortality.This association was found to be irrespective of the type of corticosteroid used.These findings suggested a need for careful consideration and management of corticosteroid dosing in treating such patients to improve clinical outcomes.

Fig. 1
Fig. 1 Schematic diagram of patient screening for inclusion and analysis

Fig. 3
Fig.3Kaplan-Meier curves of 28-day mortality for patients in the usual and higher dose corticosteroid treatment groups which included mild, moderate, severe, and critical.The diagnosis of COVID-19 was confirmed by polymerase chain reaction (PCR) or antigen testing using nasopharyngeal swabs or lower respiratory tract specimens (the sputum, transtracheal aspirates, bronchoalveolar lavage fluid).Severe or critical COVID-19 was defined if met any of the following criteria: (1) Shortness of breath with respiratory rates over 30 per minute; (2) Pulse oxygen saturation (SpO 2 ) ≤ 93% in the resting state; (3) Partial pressure of oxygen/Fraction of inspired oxygen (PaO 2 /

Table 1
Clinical characteristics of enrolled patients before and after propensity score matching PaO 2 , PFR, APACHE II score, and SOFA score were based on the worst variables recorded during the first 24 h of ICU admission CKD chronic kidney disease, HFNC high flow nasal cannula, NIPPV noninvasive positive pressure ventilation, IPPV invasive positive pressure ventilation, ECMO Extracorporeal membrane oxygenation, PFR PaO 2 /FiO 2 ratio, APACHE II score acute physiology and chronic health evaluation II score, SOFA score sequential organ failure assessment score was 61.4% (479/780), with 57.5% (299/520) in the usual dose corticosteroid treatment group and 69.2% (180/260) in the higher dose corticosteroid treatment group.Logistic regression also showed that higher doses of corticosteroid application were associated with in-ICU mortality (OR = 1.66,95%CI 1.21-2.28,p=0.002).Other outcome events including organ dysfunction in ICU stay, secondary infection and septic shock, acute kidney injury, acute myocardial injury, deep vein thrombosis and acute pulmonary embolism, acute liver injury, gastrointestinal bleeding, hyperglycemia, and the application of renal replacement therapy and ECMO support in ICU stay were not associated with higher doses of corticosteroid therapy.The detailed data have participated in Table2.

Table 3
Prednisone/prednisolone/methylprednisolone as reference in type of CS analysis CS corticosteroid, HFNC high flow nasal cannula, NIPPV noninvasive positive pressure ventilation, IPPV invasive positive pressure ventilation, ECMO Extracorporeal membrane oxygenation *